In nature a great variety of organic constituents are made up of chiral molecules with the emphasis to use the inherently stored stereochemical information within the molecules for a dedicated and most effective regulation of chemical processes. Enantiomers are chiral molecules which behave like non-superimposible mirror images of each other, whereby the configuration at the centers of chirality are determined by priority rules. In a non-chiral environment or without any chiral auxiliaries enantiomers are identical from a physicochemical point of view. However, if enantiomers get in close contact with a chiral auxiliary thus forming molecule associates, one results diastereoisomers of which the physical properties are different. This general concept can be used advantageously to distinguish between enantiomers and to set up strategies to synthesize and/or to separate enantiomers and to isolate the individual stereoisomers in enantiomerically pure form.
A one-to-one mixture of the enantiomers of a particular compound is called racemate or racemic mixture. In order to resolve this mixture to generate the two individual enantiomers two promising concepts can be followed. One relies on the preferential chemical modification or reaction of one of the enantiomers using a stereoselective reaction scheme implementing (bio)catalytic synthesis routes and synthesis concepts with chiral induction, respectively. This strategy involves stereoselective molecular recognition processes and the chiral auxiliary resigns in the chiral catalysts or chiral reactands. In the last years great progress has been made in this field to synthesize enantiomerically pure compounds (EPCs) with high chemical and stereochemical yield. However, it is still quite rare to reach EPCs with enantiomeric excess (ee) values of 99% or greater, which implies that one still may need additional methods and processes for the enantiopurification to the desired ee values.
This second strategy to observe EPCs relies on separation processes involving chiral auxiliaries, selectors (SOs) with which the individual enantiomers within their mixture are forming quasi diastereomeric transient molecule complexes or molecule associates of different physicochemical properties, including association and/or dissociation constants. The more these types of diastereomers differ in their energy content (expressed as .DELTA..DELTA.G values) the more efficient a stereoselective separation process may be established. The intermolecular binding forces active in the course of forming the diastereomeric selector (SO)--selectand (SA) molecule associates span from electrostatic interactions, including dipole-dipole interactions to hydrogen bonding, .pi.--.pi. type interactions to van der Waal type interactions in conjunction with steric parameters which may be described as steric attraction (fit) or repulsion (non-fit). Consequently and as a result of this great variability of stereodiscriminatively active SO-SA interactions the chemical constitution of selector compounds is very high. However, a successful concept relies on complementary interactions between SO and SA, which implies that for given selectands with their chemical structure optimal selectors may exist, or vice versa, with respect to the development of efficient separation methods to generate EPCs. From a general and methodological point of view fractionated crystallization methods, liquid-liquid and liquid-solid type extraction methods are most promising, including chromatographic and membrane type separation methods. Recent reviews describing the various techniques in the field are given by [S. Allenmark (Ed.), Chromatographic Enantioseparation: Methods and Applications, Wiley, New York, (1988); G. Subramanian (Ed.), A Practical Approach to Chiral Separations by Liquid Chromatography, VCH, Weinheim, (1994); J. Jacques, A. Collet, S. H. Wilen, Enantiomers, Racemates, and Resolutions, Krieger Publ. Comp., (1994);].
To summarize, the chemical structure of a chiral selector described by its overall spatial size and (supra)molecular structure, by the number of stereogenic centers and their absolute configurations, by the nature and size of the various substituents of the stereogenic centers and the conformation of the solvated compound, and by the number and types of functional groups within the compound will eventually define as a sum parameter the interaction domains of a selector compound. The selectand molecules, respectively each individual enantiomer of a pair of enantiomers, may get selectively attracted or even repulsed by the multivariate interaction sites within the SO and SA moiety, whereby the magnitude of the differences can vary from very small to great.
Within the group of prominent chiral auxiliaries and selectors to be used for enantioseparations the cinchona alkaloids proved their potential which goes back to the beginnings of stereochemistry and of chiral resolutions. Since then these compounds found a number of applications as resolving agents for the fractionated crystallization of chiral acids as diastereomeric salts [P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 2, Part I and II, Optical Resolution Information Center, Manhattan College, Riverdale, N.Y. 10471, 1981]. Among the most often used cinchonan based resolving agents are to be mentioned the naturally occurring bases quinine, quinidine, cinchonine and cinchonidine as well as their synthetic derivatives, the respective 1-methyl or 1-benzyl quaternized salts which all leave the hydroxyl group at the chiral C.sub.9 carbon non-substituted. However, it should be mentioned at this point that quinine and quinidine as well as their ester derivatives are known to be chemically relatively labile [Y. Yanuka et al., Tetrahedron, 43 (1987) 911] which prevented them from their more frequent use as chiral auxiliaries in crystallization protocols. Cinchona alkaloids have also been employed successfully for diverse stereodiscriminating techniques in the field of liquid-phase separations. In this context one of the most popular concepts for the discrimination of enantiomers has become the direct HPLC enantioseparation method with a chiral additive to the mobile phase together with an achiral stationary phase (CMP) or with an achiral mobile phase together with a chiral stationary phase (CSP). Also cinchona-alkaloids have been utilized in accordance with these two concepts, but so far with minor success. In all cases reported in literature, the secondary hydroxyl group grafted to the C.sub.9 carbon was unsubstituted or was esterified (acetylated, p-chlorobenzoylated). Such chiral selectors were either added to the mobile phase [A. Karlsson et al., Chirality, 4 (1992) 323] or immobilized onto silica [P. Salvadori et al., Tetrahedron, 43 (1987) 4969; Chirality, 4 (1992) 43; P. N. Nesterenko et al., J. Chromatogr. A, 667 (1994) 19]. As stated above these selectors suffered also from chemical instability which restricted their applicability. Very recently, native quinine was employed also as an additive to the running buffer in non-aqueous capillary zone electrophoresis and used as chiral discrimination auxiliary or selector for the separation of the enantiomers of 3,5-dinitrobenzoylated amino acids and other chiral acids [A. M. Stalcup et al., J. Microcolumn Separations, 8(2), (1996) 145].
Besides in the stereoselective separation methods, cinchona alkaloids and derivatives thereof, respectively, play an important role also in the field of stereoselective synthesis as homogeneous and heterogenous chiral auxiliaries or ligands in asymmetric catalysis. The most effective and important ones are cited in [H. Brunner et al., Handbook of Enantioselective Catalysis, Vol. I and II, VCH, Weinheim, New York, 1993; H.-U. Blaser, Chem. Rev., 92 (1992) 935]. Mostly, the hydroxyl group of the chiral C.sub.9 carbon remained unsubstituted, since the hydroxyl group is presumed to play a key role in the diastereomeric complex formation of the transition states. On the other side, from the group of Sharpless we know that O-derivatized cinchona alkaloids also act as excellent chiral ligands in asymmetric syntheses, e.g., in the osmium-catalyzed asymmetric dihydroxylation or aminohydroxylation of olefins [Sharpless et al., WO 92/20677]. This group found that particularly ether type derivatives of the alkaloids, especially of dihydroquinine and dihydroquinidine, gave the highest optical yields and reaction rates in the course of osmium catalyzed addition reactions of olefinic compounds [H. C. Kolb et al., J. Am. Chem. Soc., 116 (1994) 12783. Other derivatives tested concerned ester analogues of the dihydroalkaloids (e.g. p-chlorobenzoyl esters) but also some carbamate derivatives, namely N, N-dimethyl, N-methyl-N-phenyl, N-phenyl and N, N-diphenyl carbamates of cinchona alkaloids have been described [Sharpless et al., WO 92/20677]. However, these carbamates of dihydroquinidine (the 11 position remained unsubstituted; the vinyl group of the alkaloid had to be hydrogenated to be a useful catalyst for the dihydroxylation of olefins) employed as chiral auxiliaries in stereoselective catalysis reactions did express relatively poor chiral induction compared to the ether derivatives. The ester and amide group did obviously not support a pronounced stereocontrolled recognition process in the course of catalytic asymmetric dihydroxylation of olefines. However, for stereodiscrimination processes with respect to separation technologies cinchona alkaloid carbamates, ureas, amides, etc., have not been utilized and described, but these cinchona alkaloid derivatives may provide special features by manipulating and optimizing the substitution pattern and thus also improving considerably the chemical and stereochemical stability of cinchona alkaloids.
In this context and in order to expand the spectrum of cinchona based selectors but with positionally switched hydrogen donor-acceptor functionalities close to the chiral C.sub.9 position 9-amino (9-deoxy) cinchona derivatives have also been made subject of the present invention. Hence, only little interest has been directed towards the diamines derived from cinchona alkaloids by replacing the 9-hydroxyl function by an amino group. The first synthesis described by [S. Frankel, C. Tritt, M. Mehrer and M. Herschman, Chem.Ber. 58, 549 (1925)] involves treatment of potassium phthalimide or sodium benzenesulfonamide with quinine chloride at elevated temperatures in vacuum to give in the first step the corresponding phthalimide and benzenesulfonamide which were characterized as their picrates. Subsequent acidic hydrolysis of the amide gave the corresponding amine which was converted to sulfate and picrate. However, since the synthetic strategies employed involve conditions which are known to lead to isomerization at C.sub.9 or re-arrangement of the quinuclidine ring [P. Rabe, Liebigs Ann. Chem, 561, 132 (1948)] the stereochemistry of the amine and amides, respectively, reported by Frankel et al. is difficult to establish. [G. R. Pettit and S. K. Gupta, J.Chem. Soc. ( C ) 1208 (1968)] reported a different approach based on LiAlH4 reduction of oximes of quinidinone and cinchonidinone Most recently, an efficient synthesis of 9-amino-(9-deoxy)-cinchona alkaloids based on Mitsunobu chemistry has been developed and the stereochemistry of the products established by X-ray crystallography [H. Brunner, J. Bugler and B. Nuber, Tetrahedron: Asymmetry, Vol.6, 7, 1699 (1995)]. However, up to date no application of these cinchona alkaloids derived diamines in chiral discrimination using chromatographic methods or membrane technologies or solid-phase extraction methods or crystallographic methods has been described.